Ivabradine, (+)-3-[3-[N-[4,5-Dimethoxybenzocyclobutan-1(S)-ylmethyl]-N-methylamino]propyl]-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one, is represented by the structural formula (I):

Ivabradine, and addition salts thereof with a pharmaceutically acceptable acid, and more especially its hydrochloride, have very valuable pharmacological and therapeutic properties, especially bradycardic properties, making those compounds useful in the treatment or prevention of various clinical situations of myocardial ischaemia such as angina pectoris, myocardial infarct and associated rhythm disturbances, and also in various pathologies involving rhythm disturbances, especially supraventricular rhythm disturbances, and in heart failure.
Ivabradine is currently marketed with trade name Corlentor® and Procolaran® for treatment of chronic stable angina pectoris in coronary artery disease patients with normal sinus rhythm.
The preparation and the therapeutic use of ivabradine and addition salts thereof with a pharmaceutically acceptable acid, and more especially its hydrochloride, have been described in the European patent specification EP0534859.
EP0534859 describes a synthesis process for ivabradine and its hydrochloride salt. It is disclosed a product recrystallized in acetonitrile with its melting point Mp: 135-140° C.
EP1589005 discloses the crystalline Form α of ivabradine hydrochloride, characterized by PXRD, and a process for its preparation.
EP1695965 discloses the crystalline Form β, a tetrahydrate form of ivabradine hydrochloride, characterized by PXRD, and a process for its preparation.
EP1695710 discloses the crystalline Form βd of ivabradine hydrochloride, characterized by PXRD, and a process for its preparation.
EP1707562 discloses the crystalline Form γ, a monohydrate form of ivabradine hydrochloride, characterized by PXRD, and a process for its preparation.
EP1695709 discloses the crystalline Form γd of ivabradine hydrochloride, characterized by PXRD, and a process for its preparation.
EP1775288 discloses the crystalline Form δ, a hydrated form of ivabradine hydrochloride, characterized by PXRD, and a process for its preparation.
EP1775287 discloses the crystalline Form δd of ivabradine hydrochloride, characterized by PXRD, and a process for its preparation.
WO2008/125006 discloses a crystalline form of ivabradine hydrochloride, characterized by PXRD, and a process for its preparation.
CN101768117 discloses a crystalline form of ivabradine hydrochloride, characterized by PXRD, and a process for its preparation.
CN101805289 discloses the crystalline Form ω of ivabradine hydrochloride, characterized by PXRD, and a process for its preparation.
WO2011/098582 discloses three crystalline forms of ivabradine hydrochloride, characterized by PXRD, and a process for its preparation.
WO2008/146308, CN101463008, CN101597261 and CN102050784 disclose amorphous form of ivabradine hydrochloride and a process for its preparation.
The polymorphic behaviour of drugs can be of crucial importance in pharmacy and pharmacology. Polymorphism is the ability of a substance to crystallize in different crystal modifications, each of them having the same chemical structure but different arrangements or conformations of the molecules in the crystal lattice. The differences in physical properties exhibited by polymorphs affect pharmaceutical parameters such as storage stability, compressibility and density (important in formulation and product manufacturing), and dissolution rates (an important factor in determining bio-availability). Differences in stability can result from changes in chemical reactivity or mechanical changes or both. For example, a dosage form originating from one polymorph might discolor more rapidly when compound to another from a different polymorph. Or tablets might crumble on storage as a kinetically favoured polymorph spontaneously converts into a thermodynamically more stable polymorphic form. As a result of solubility/dissolution differences, in the extreme case, some polymorphic transitions may result in lack of potency or, at the other extreme, toxicity. In addition, the physical properties of the crystal may be important in processing: for example, one polymorph might be more likely to form solvates or might be difficult to filter and wash free of impurities.
The most important solid state property of a pharmaceutical substance is its rate of dissolution in aqueous fluid. The rate of dissolution of an active ingredient in a patient's gastric fluid may have therapeutic consequences as it imposes an upper limit on the rate at which an orally-administered active ingredient reaches the blood stream. The solid state polymorphic form of a compound may also affect its behaviour on compaction and its storage stability.
These practical physical characteristics are influenced by the conformation and orientation of molecules in the unit cell, which defines a particular polymorphic form of a substance. The polymorphic form may give rise to thermal behaviour different form that of the amorphous material (or) another polymorphic form.
The discovery of new polymorphic forms of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic.
Usually the most stable polymorphic form is preferred in a marketed formulation, because any other polymorphs are metastable and may therefore transform to the more stable form. Overlooking the most stable polymorph may cause failure of a marketed product due to phase transformation during storage. A late-appearing stable polymorph can have a great impact on development timelines. Although metastable forms may survive years if a considerable activation energy barrier has to be overcome in moving from the metastable state to the stable state, this activation-energy barrier may be reduced by moisture, catalysts, impurities, excipients or temperature and the transformation into the stable form occurs spontaneously. Seeds of the stable form may also accelerate transformations. Therefore using a thermodynamically unstable modification in the production of tablets is sometimes the reason why unwanted changes take place in such formulations after a time of storage. Therefore, there is a need for a thermodynamically stable polymorphic form of ivabradine hydrochloride and methods of its preparation.
A method described by Haleblian and McCrone can be used to determine the most stable polymorph at room temperature. This method utilizes the fact that the most stable polymorph will also be the less soluble at a given temperature and pressure. If crystals of both polymorphs are present in a saturated solution, the most stable form will grow at the expense of the less stable one. This method is called the solution phase transformation or solvent mediated transformation.
Therefore, there is a demand for alternative pure and crystalline forms of ivabradine hydrochloride which would be suitable for use in the pharmaceutical industry and, in particular, allow easy production of ivabradine preparations in solid form meeting strict pharmaceutical standards, such as tablets, capsules, chewable tablets, powders, etc. for oral administration.
To prepare pharmaceutical compositions containing ivabradine hydrochloride Form IV for administration to mammals in accordance with exacting health registration requirements of the U.S. and international health registration authorities, e.g. the FDA's Good Manufacturing Practices (“GMP”) requirements, there is a need to produce ivabradine hydrochloride Form IV in as pure a form as possible, especially a form having constant physical properties.